Effects of Preactivated Autologous T Lymphocytes on CD80, CD86 and CD95 Expression by Chronic Lymphocytic Leukemia B Cells

2003 ◽  
Vol 44 (11) ◽  
pp. 1963-1971 ◽  
Author(s):  
Ciro Romano ◽  
Umberto De Fanis ◽  
Ausilia Sellitto ◽  
Liliana Dalla Mora ◽  
Federico Chiurazzi ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
T Lymphocytes ◽  
Lymphocytic Leukemia

scholarly journals Lactic dehydrogenase in normal and leukemia lymphocyte subpopulations: evidence for the presence of abnormal T cells and B cells in chronic lymphocytic leukemia

Blood ◽  
1981 ◽  
Vol 57 (2) ◽  
pp. 324-327 ◽  
Author(s):  
P Rambotti ◽  
S Davis
Keyword(s):  
T Cells ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
T Lymphocytes ◽  
B Lymphocytes ◽  
Lactic Dehydrogenase ◽  
Isozyme Pattern ◽  
Lymphocyte Subpopulations ◽  
Lymphocytic Leukemia ◽  
Ldh Activity

Abstract Lactic dehydrogenase (LDH) was quantitated and the isozyme pattern studied in lymphocyte subpopulations from normal people and patients with chronic lymphocytic leukemia (CLL). Normal T lymphocytes differed from normal B lymphocytes in having greater total LDH activity (597.2 versus 252.1). Total LDH activity in CLL T cells (347.1) was lower than normal T cells., but not significantly different than normal B cells. Total LDH activity in CLL B cells (124.6) was lower then normal B cells and normal T cells. The isozyme pattern of normal T lymphocytes showed a higher activity in the LDH-1 band (26.7% versus 5.4%) but showed a lower activity in LDH-5 band (4.3% versus 16.3%) compared to normal B cells. Chronic lymphocytic leukemia T cells could be distinguished from CLL B cells by a high LDH-5 band (22.3% versus 7.6%) and from normal T cells by a high LDH-5 band (22.3% versus 4.3%) and a low LDH-1 band (7.3% versus 26.7%). CLL B cells could be distinguished from normal B cells by a low LDH-5 band (7.6% versus 16.3%). Thus, the LDH isozyme pattern distinguishes normal T lymphocytes from normal B lymphocytes, and normal T and B lymphocytes from CLL T and B lymphocytes.

The effect of alemtuzumab maintenance therapy on B and T lymphocytes in chronic lymphocytic leukemia

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7092-7092
Author(s):  
M. S. Kaufman ◽  
N. Driscoll ◽  
C. Johnson ◽  
A. Caramanica ◽  
D. Janson ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
T Lymphocytes ◽  
Maintenance Therapy ◽  
Cd4 T Cells ◽  
Opportunistic Infections ◽  
Lymphocytic Leukemia ◽  
Blood Levels ◽  
Time Point

7092 Background: We are conducting a pilot, exploratory study of the potential value of alemtuzumab(alem) in maintenance therapy of previously treated chronic lymphocytic leukemia (CLL) patients(pts) after they have achieved stable disease or partial remission with chemo or chemo-immunotherapy. We present the results of serially monitored CD19+ (B)lymphocytes and CD4+ (T) lymphocytes on eight evaluable patients. Methods: 30mg doses of alem were administered SC to all patients at the following schedule: wkly for 8 doses (8 wks), followed by q2 wks for 8 doses(16 wks), followed by q3 wks for 8 doses (24 wks). This schedule provides a total of 48 wks of maintenance treatment with alem. Patients received standard prophylaxis with sulfamethoxizole and acyclovir with regular CMV monitoring by quantitative PCR. Results: In the table we present data on the pattern of decrease in blood CD19+(B) cells and CD4+ (T) cells on eight evaluable pts at different time points after starting alem maintenance. Because flow cytometry was not done on all pts at each time point, the number of pts contributing to the calculation of mean counts at each given time point is variable. CD19+(B) cells were markedly reduced to 37% of baseline consistently, from 8 wks onward. CD4+(T) cells, on the other hand, were consistently higher than 50% of the baseline after 8 wks. No opportunistic infections were seen in any pt and treatment was well tolerated. Conclusion: These results from a single institution based pilot study demonstrate that alem used in maintenance schedule is effective in keeping the blood levels of CD19+(B) cells extremely low without concordant suppression of CD4+(T) lymphocytes. No significant financial relationships to disclose. [Table: see text]

CD40 activation does not protect chronic lymphocytic leukemia B cells from apoptosis induced by cytotoxic T lymphocytes

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 3853-3858 ◽  
Author(s):  
Peter Chu ◽  
William G. Wierda ◽  
Thomas J. Kipps
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Lymphocytic Leukemia ◽  
Target Cells ◽  
Apoptosis Pathway ◽  
Granule Exocytosis ◽  
Concanamycin A ◽  
Cd40 Activation

Cytotoxic T lymphocytes (CTLs) can kill target cells by the granule/exocytosis pathway or the Fas-mediated apoptosis pathway. The sensitivity of chronic lymphocytic leukemia (CLL) B cells to CTL-mediated apoptosis before and after CD40 activation was examined. Resting or CD40-activated CLL cells were found to be equally sensitive to class I–restricted CTL-mediated killing. Despite expressing CD95, the CD40-activated CLL target cells were found to be resistant to apoptosis induced by CH11, an IgM CD95 monoclonal antibody (mAb). Consistent with this, inhibitors of caspases, which are involved in the Fas-induced apoptotic pathway (eg, N-carbobenzoxy-Val-Ala-Asp fluoromethyl ketone [z-VAD-fmk]), were unable to block destruction of CLL target cells by CTL. In addition, preincubation of the effector T cells with the anti-Fas ligand mAb NOK-2 failed to inhibit their subsequent ability to kill CLL target cells. On the other hand, CTL activity was blocked by inhibitors of the granule exocytosis pathway such as ethylene-glyco-tetra-acetic acid or concanamycin A. These results indicate that CD40 activation does not impair the sensitivity of CLL cells to Fas-independent CTL-mediated apoptosis.

CD40 activation does not protect chronic lymphocytic leukemia B cells from apoptosis induced by cytotoxic T lymphocytes

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 3853-3858 ◽  
Author(s):  
Peter Chu ◽  
William G. Wierda ◽  
Thomas J. Kipps
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Lymphocytic Leukemia ◽  
Target Cells ◽  
Apoptosis Pathway ◽  
Granule Exocytosis ◽  
Concanamycin A ◽  
Cd40 Activation

Abstract Cytotoxic T lymphocytes (CTLs) can kill target cells by the granule/exocytosis pathway or the Fas-mediated apoptosis pathway. The sensitivity of chronic lymphocytic leukemia (CLL) B cells to CTL-mediated apoptosis before and after CD40 activation was examined. Resting or CD40-activated CLL cells were found to be equally sensitive to class I–restricted CTL-mediated killing. Despite expressing CD95, the CD40-activated CLL target cells were found to be resistant to apoptosis induced by CH11, an IgM CD95 monoclonal antibody (mAb). Consistent with this, inhibitors of caspases, which are involved in the Fas-induced apoptotic pathway (eg, N-carbobenzoxy-Val-Ala-Asp fluoromethyl ketone [z-VAD-fmk]), were unable to block destruction of CLL target cells by CTL. In addition, preincubation of the effector T cells with the anti-Fas ligand mAb NOK-2 failed to inhibit their subsequent ability to kill CLL target cells. On the other hand, CTL activity was blocked by inhibitors of the granule exocytosis pathway such as ethylene-glyco-tetra-acetic acid or concanamycin A. These results indicate that CD40 activation does not impair the sensitivity of CLL cells to Fas-independent CTL-mediated apoptosis.

scholarly journals Interleukin 2 (IL 2) and interferon-gamma production by T lymphocytes from patients with B-chronic lymphocytic leukemia: evidence that normally released IL 2 is absorbed by the neoplastic B cell population

Blood ◽  
1985 ◽  
Vol 66 (3) ◽  
pp. 614-619 ◽  
Author(s):  
R Foa ◽  
M Giovarelli ◽  
C Jemma ◽  
MT Fierro ◽  
P Lusso ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
T Lymphocytes ◽  
B Cell ◽  
T Lymphocyte ◽  
Interleukin 2 ◽  
Lymphocytic Leukemia ◽  
Ifn Gamma ◽  
Culture Supernatants

Abstract The capacity of T lymphocytes from patients with B cell chronic lymphocytic leukemia (B-CLL) to release interleukin 2 (IL 2) and interferon (IFN)-gamma was assessed following various stimuli. The spontaneous release of IL 2 and IFN-gamma was practically absent both with B-CLL and normal T lymphocytes. By contrast, after stimulation with phytohemagglutinin (PHA) or with PHA plus 12-O- tetradecanoylphorbol-13-acetate, the production of IL 2 and IFN-gamma by B-CLL T lymphocytes was similar to that of normal T lymphocytes, irrespective of the reversed T lymphocyte subset distribution (OKT4/OKT8 ratio) observed in B-CLL. However, the titer of IL 2 was greatly reduced when autologous leukemic B cells were added to the culture system. Unlike IL 2, the presence of leukemic B cells did not affect the titer of IFN-gamma in the culture supernatants. The indication that IL 2 may be adsorbed in vivo by the neoplastic B cells was further confirmed by the demonstration of the IL 2 receptor (revealed by anti-Tac monoclonal antibody) on the leukemic B cells, particularly following mitogenic stimulation, and by the evidence that exogenous IL 2 can be directly absorbed by untreated B-CLL T lymphocytes to release IFN-gamma and IL 2 is preserved, but that IL 2 may be rapidly removed by the neoplastic B-CLL cells, thus contributing to the well-documented T lymphocyte abnormalities present in this disease.

scholarly journals Lactic dehydrogenase in normal and leukemia lymphocyte subpopulations: evidence for the presence of abnormal T cells and B cells in chronic lymphocytic leukemia

Blood ◽  
1981 ◽  
Vol 57 (2) ◽  
pp. 324-327
Author(s):  
P Rambotti ◽  
S Davis
Keyword(s):  
T Cells ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
T Lymphocytes ◽  
B Lymphocytes ◽  
Lactic Dehydrogenase ◽  
Isozyme Pattern ◽  
Lymphocyte Subpopulations ◽  
Lymphocytic Leukemia ◽  
Ldh Activity

Lactic dehydrogenase (LDH) was quantitated and the isozyme pattern studied in lymphocyte subpopulations from normal people and patients with chronic lymphocytic leukemia (CLL). Normal T lymphocytes differed from normal B lymphocytes in having greater total LDH activity (597.2 versus 252.1). Total LDH activity in CLL T cells (347.1) was lower than normal T cells., but not significantly different than normal B cells. Total LDH activity in CLL B cells (124.6) was lower then normal B cells and normal T cells. The isozyme pattern of normal T lymphocytes showed a higher activity in the LDH-1 band (26.7% versus 5.4%) but showed a lower activity in LDH-5 band (4.3% versus 16.3%) compared to normal B cells. Chronic lymphocytic leukemia T cells could be distinguished from CLL B cells by a high LDH-5 band (22.3% versus 7.6%) and from normal T cells by a high LDH-5 band (22.3% versus 4.3%) and a low LDH-1 band (7.3% versus 26.7%). CLL B cells could be distinguished from normal B cells by a low LDH-5 band (7.6% versus 16.3%). Thus, the LDH isozyme pattern distinguishes normal T lymphocytes from normal B lymphocytes, and normal T and B lymphocytes from CLL T and B lymphocytes.

Prognostic Implications of PIM-2 Expression in Samples from Patients with Chronic Lymphocytic Leukemia and Impact in the Sensitivity to the Pan-PIM Kinase Inhibitor PIM447

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2923-2923
Author(s):  
Ana Alicia López-Iglesias ◽  
Irena Misiewicz-Krzeminska ◽  
Ignacio Criado ◽  
Miguel Alcoceba ◽  
Susana Hernández-García ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
T Lymphocytes ◽  
Cell Lines ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Ex Vivo ◽  
Lymphocytic Leukemia ◽  
Protein Levels ◽  
Pim Kinases

Abstract Background and objectives. PIM kinases (PIM1, PIM2, PIM3) are proteins known to be overexpressed in several hematological malignancies. In particular, in chronic lymphocytic leukemia (CLL) they are involved in cell survival, resistance to apoptosis (especially PIM2 and PIM3) and interactions with the microenvironment (PIM1). The aim of this study was dual: I) to evaluate the preclinical efficacy of PIM447, a pan PIM kinase inhibitor, in CLL and to study potential synergies with other drugs; and II) to evaluate the expression of PIM-kinases in different stages of the disease and correlate it with the prognosis and the sensitivity to the drug. Methods. Peripheral blood samples from untreated patients with different stages of the disease (monoclonal B lymphocytosis (MBL), stable CLL not requiring treatment (sCLL), and active CLL requiring treatment (aCLL)) were collected after informed consent. The ex vivo efficacy of PIM447 was analyzed by flow cytometry with annexin V in these samples. Moreover, PIM447 efficacy was also analyzed in two cell lines (MEC-1 and JVM-2) by MTT assay. Synergy with other drugs effective in CLL (bendamustine and fludarabine) was evluated with the calcusyn software. Protein levels of PIM Kinase proteins were evaluated by capillary electrophoresis immunoassay (WESTM ProteinSimple) in monoclonal B cells purified by CD19 selection with anti-CD19 magnetic microbeads and the autoMacs Cell separator (both from Miltenyi Biotec) from a subset of patients. Results. The pan PIM inhibitor, PIM447 was active in both cell lines tested, MEC-1 (IC50 5μM) and JVM2 (IC50 7μM), and also in monoclonal B cells from freshly isolated patients samples (sCLL=11; aCLL=5), with no difference in sensitivity between the different stages of the disease (IC50 of 4,8 μM and 4,7 μM for sCLL and aCLL respectively). There was a clear therapeutic window as treatment with PIM447 at doses toxic for monoclonal B cells, preserved T lymphocytes (figure 1) (median % of apoptosis for B cells and T lymphocytes respectively of 23 vs 20 at 5μM and 87 vs 35 at 10 μM). Moreover, PIM447 demonstrated to potentiate the activity of both bendamustine and fludarabine, being especially synergistic with this last one (combination index 0.1-0.6). A second objective was to analyze PIM2 protein expression by western blot in monoclonal B cells from these samples and correlate it with clinical and biological features. Up to now, it has been evaluated in 18 samples (MBL=4; sCLL=8; aCLL=6,). All of them expressed PIM-2. Expression levels of this protein were significantly higher in active CLL as compared with indolent stages of the disease (p=0,012). Patients with an unmutated IGHV status also displayed higher levels of PIM2 (p=0,01). Finally, samples with high PIM2 levels were slightly more resistant to PIM447 as compared with samples with lower protein levels (IC50 of 7,7 μM vs 5 μM, respectively). We are currently completing the analysis of the PIM2 levels of remaining samples and we are also measuring the levels of PIM1 protein, what will be available at the meeting. Conclusions: PIM-Kinase inhibition with PIM447 is effective in vitro in CLL cell lines and ex vivo in samples from patients. It synergizes with other agents especially fludarabine. PIM2 protein levels correlated with the clinical activity of CLL and with the mutational state of IGHV. Although all patients appear sensitive ex vivo to PIM447, further work is required to define PIM2 expression as a marker of sensitivity. Figure 1. Figure 1. Disclosures Ocio: Array BioPharma: Consultancy, Research Funding; Celgene: Honoraria, Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy; Mundipharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; MSD: Research Funding; Pharmamar: Consultancy, Research Funding; Jassen: Honoraria.

scholarly journals Interleukin 2 (IL 2) and interferon-gamma production by T lymphocytes from patients with B-chronic lymphocytic leukemia: evidence that normally released IL 2 is absorbed by the neoplastic B cell population

Blood ◽  
1985 ◽  
Vol 66 (3) ◽  
pp. 614-619 ◽  
Author(s):  
R Foa ◽  
M Giovarelli ◽  
C Jemma ◽  
MT Fierro ◽  
P Lusso ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
T Lymphocytes ◽  
B Cell ◽  
T Lymphocyte ◽  
Interleukin 2 ◽  
Lymphocytic Leukemia ◽  
Ifn Gamma ◽  
Culture Supernatants

The capacity of T lymphocytes from patients with B cell chronic lymphocytic leukemia (B-CLL) to release interleukin 2 (IL 2) and interferon (IFN)-gamma was assessed following various stimuli. The spontaneous release of IL 2 and IFN-gamma was practically absent both with B-CLL and normal T lymphocytes. By contrast, after stimulation with phytohemagglutinin (PHA) or with PHA plus 12-O- tetradecanoylphorbol-13-acetate, the production of IL 2 and IFN-gamma by B-CLL T lymphocytes was similar to that of normal T lymphocytes, irrespective of the reversed T lymphocyte subset distribution (OKT4/OKT8 ratio) observed in B-CLL. However, the titer of IL 2 was greatly reduced when autologous leukemic B cells were added to the culture system. Unlike IL 2, the presence of leukemic B cells did not affect the titer of IFN-gamma in the culture supernatants. The indication that IL 2 may be adsorbed in vivo by the neoplastic B cells was further confirmed by the demonstration of the IL 2 receptor (revealed by anti-Tac monoclonal antibody) on the leukemic B cells, particularly following mitogenic stimulation, and by the evidence that exogenous IL 2 can be directly absorbed by untreated B-CLL T lymphocytes to release IFN-gamma and IL 2 is preserved, but that IL 2 may be rapidly removed by the neoplastic B-CLL cells, thus contributing to the well-documented T lymphocyte abnormalities present in this disease.

THE ROLE OF THE GENETIC ABNORMALITIES, EPIGENETIC AND microRNA IN THE PROGNOSIS OF CHRONIC LYMPHOCYTIC LEUKEMIA

2018 ◽  
Vol 40 (4) ◽  
pp. 261-267 ◽  
Author(s):  
K Tari ◽  
Z Shamsi ◽  
H Reza Ghafari ◽  
A Atashi ◽  
M Shahjahani ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Kinase Inhibitors ◽  
Bone Marrow Involvement ◽  
P53 Mutation ◽  
Lymphocytic Leukemia ◽  
Gene Promoters ◽  
Epigenetic Changes ◽  
Genetic Changes ◽  
Trisomy 12

Chronic lymphocytic leukemia (CLL) is increased proliferation of B-cells with peripheral blood and bone marrow involvement, which is usually observed in older people. Genetic mutations, epigenetic changes and miRs play a role in CLL pathogenesis. Del 11q, del l17q, del 6q, trisomy 12, p53 and IgVH mutations are the most important genetic changes in CLL. Deletion of miR-15a and miR-16a can increase bcl2 gene expression, miR-29 and miR-181 deletions decrease the expression of TCL1, and miR-146a deletion prevents tumor metastasis. Epigenetic changes such as hypo- and hypermethylation, ubiquitination, hypo- and hyperacetylation of gene promoters involved in CLL pathogenesis can also play a role in CLL. Expression of CD38 and ZAP70, presence or absence of mutation in IgVH and P53 mutation are among the factors involved in CLL prognosis. Use of monoclonal antibodies against surface markers of B-cells like anti-CD20 as well as tyrosine kinase inhibitors are the most important therapeutic approaches for CLL.

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